The purpose of this proposal is to prepare and analyze a family of inhibitors of the enzyme, HIV-1 protease. Effective inhibitors of HIV-1 protease are potential therapeutic agents since this enzyme is essential in the life cycle of the virus. The synthesis of mechanism based, transition state inhibitors is one route to the development of such inhibitors. The proposed family of compounds, the peptide sulfonamides, can be prepared by relatively standard chemical means. They are compatible with the known three dimensional structure and sequence specificity of the enzyme. Peptide sulfonamides are tetrahedral compounds that resemble the tetrahedral transition state believed to be present in the aspartate protease mediated protein hydrolyses. Peptide sulfonamides are similar to the peptide alcohols known to be aspartate protease inhibitors, but contain two oxygen atoms on the central tetrahedral atom, not one. Both the design and synthesis of these inhibitors are facilitated by the extensive previous kinetic and structural studies of other aspartate proteases. Both renin and pepsin have been investigated using a wide variety of synthetic and natural substrates and inhibitors. Interest in this family of compounds has increased dramatically since the discovery of the retroviral aspartate proteases, especially that produced by the human immunodeficiency virus. This enzyme, critical to the maturation of the virion, has already been the study of both X-ray crystallographic and point of cleavage studies in other laboratories. The specific structures of the peptide sulfonamides was proposed after utilizing VAX-based molecular modeling programs in conjunction with the crystal structure of the aspartate protease and the structure of the protease-natural substrate complex, both of which are available on the Brookhaven National Laboratories database. Synthesis of these inhibitors combines standard peptide chemistry with the already well known chemistry of the sulfonamides. Assay of the inhibitors will be done initially utilizing a recombinant HIV-1 protease and a nonapeptide substrate. The rate of reaction will be determined on reverse phase HPLC. Both the purified enzyme and the substrate are already in our laboratories.